Coronary artery disease constitutes a major cause of morbidity and mortality throughout the world, especially in the United States and Europe. Percutaneous transluminal coronary angioplasty (e.g., balloon angioplasty, with our without intracoronary stenting) is now a common and successful therapy for such disease, performed hundreds of thousands of times per year in the United States alone. However, restenosis occurs in as many as one-third to one-half of such revascularization procedures, usually within six months of the angioplasty procedure. The economic cost of restenosis has been estimated at $2 billion annually in the United States alone. [Feldman et al., Cardiovascular Research, 32: 194-207 (1996), incorporated herein by reference.] Autopsy and atherectomy studies have identified intimal hyerplasia as the major histologic component of restenotic lesions. [Cerek et al., Am. J. Cardiol., 68: 24C-33C (1991).]
Restenosis also remains a clinical concern in angioplasty that is performed in peripheral blood vessels. Likewise, stenosis is a clinical concern following transplantation of blood vessels (e.g., grafted veins and grafted artificial vessels) for cardiac bypass therapy or for treatment of peripheral ischemia or intermittent claudication, for example (e.g., above-knee femoro-popliteal arterial bypass grafts).
Mazur et al., Texas Heart Institute Journal, 21; 104-111 (1994) state that restenosis is primarily a response of the artery to the injury caused by percutaneous coronary angioplasty, which disrupts the intimal layer of endothelial cells and underlying smooth muscle cells of the media. The authors state that multiple growth factors secreted by platelets, endothelial cells, macrophages, and smooth muscle cells are mechanistically involved in the restenosis process, and that proliferation of smooth muscle cells constitutes a critical pathogenetic feature. According to the authors, this smooth muscle cell proliferation has proven refractory to mechanical and pharmacologic therapy. More recently, others have called into question whether smooth muscle cell proliferation is of penultimate importance in restenosis. See Libby, Circ. Res., 82: 404-406 (1998).
Narins et al, Circulation, 97: 1298-1305 (1998) review the use of intracoronary stents and their benefits and limitations in preventing restenosis. Debbas et al., American Heart Journal, 133: 460-468 (1997) discuss stenting within a stent to treat in-stent restenosis.
Chang & Leiden, Semin. Intervent. Cardiol., 1: 185-193 (1996), incorporated herein by reference, review somatic gene therapy approaches to treat restenosis. Chang and Leiden teach that replication-deficient adenoviruses comprise a promising and safe vector system for gene therapy directed toward prevention of restenosis, because such viruses can efficiently infect a wide variety of cell types, including vascular smooth muscle cells; such viruses can be produced at high titers (e.g., 1010-1012 plaque forming units per milliliter); such viruses can accommodate a transgene insert of, e.g., 7-9 kilobases (kb) in size; such viruses can be delivered percutaneously through standard catheters; and such viruses do not integrate into the host genome. Both Chang & Leiden and Feldman et al., supra, also review cytotoxic and cytostatic gene therapy approaches, designed to kill or arrest proliferating vascular smooth muscle cells thought to be responsible for neointimal formations that characterize restenosis.
Riessen & Isner, J. Am. Coll. Cardiol., 23:1234-1244 (1994), incorporated by reference, review devices for intravascular drug delivery and vectors for intravascular gene therapy.
Cerek et al., Am. J. Cardiol., 68: 24C-33C (1991) suggest prevention of restenosis by inhibiting growth-factor-mediated healing of arterial injury. Potential roles of platelet-derived growth factor (PDGF), thrombospondin, insulin-like growth factor 1 (IGF-1), fibroblast growth factors (FGF's), transforming growth factor alpha (TGF-α) and beta (TGF-β), epidermal growth factor (EGF) are discussed.
Isner & Asahara, International Patent Publication No. WO 98/19712, incorporated herein by reference, suggest treating injured blood vessels and accelerating reendothelialization following angioplasty by isolating a patient's endothelial progenitor cells and re-administering such cells to the patient. The authors suggest that the effectiveness of using an angiogenesis-promoting growth factor, such as vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF), may be limited by the lack of endothelial cells on which the VEGF or bFGF will exert its effect.
Martin et al., International Patent Publication No. WO 98/20027 suggest the use of VEGF gene or protein to treat or prevent stenosis or restenosis of a blood vessel. The authors suggest that any beneficial effect of VEGF arises from a different mechanism of action than the mechanism underlying an activity of VEGF related to stimulating re-endothelialisation in cases where the endothelium has been damaged.
Callow et al., Growth Factors, 10: 223-228 (1994) state that intravenous injection of vascular permeability factor (a.k.a. VEGF) into rabbits that had been subjected to balloon angioplasty-induced endothelial denudation resulted in increased regeneration of endothelium compared to a control. The authors also stated that basic fibroblast growth factor (bFGF) is effective at promoting re-endothelialization, but that such re-endothelialization is accompanied by increases in neointimal lesion size.
Asahara et al., Circulation, 94: 3291-3302 (Dec. 15, 1996) state that local, percutaneous catheter delivery of a CMV-human-VEGF165 transgene achieved accelerated re-endothelialization in balloon-injured rabbits, and resulted in diminished intimal thickening. In a report by a related group of authors, Van Belle et al., J. Am. Coll. Cardiol., 29:1371-1379 (May, 1997) state that stent endothelialization was accelerated by delivery of a CMV-human-VEGF165 transgene and was accompanied by attenuation of intimal thickening.
Morishita et al., J. Atherosclerosis and Thrombosis, 4(3): 128-134 (1998) state that hepatocyte growth factor (HGF) has a mitogenic activity on human endothelial cells more potent than VEGF, and hypothesized that HGF gene therapy may have potential therapeutic value for the treatment of cardiovascular diseases such as restenosis after angioplasty. Morishita et al. also state that there is little knowledge about growth factors that stimulate only endothelial cells, but not vascular smooth muscle cells.
DeYoung & Dichek, Circ. Res., 82: 306-313 (1998) state that VEGF gene delivery does not currently appear destined for application to human coronary restenosis, and that two independent studies suggest that VEGF delivery may actually worsen arterial intimal hyperplasia.
Brown et al., U.S. Pat. No. 5,795,898, suggest using an inhibitor of PDGF, FGF, EGF, or VEGF signaling to suppress accelerated atherogenesis involved in restenosis of coronary vessels or other arterial vessels following angioplasty.
The foregoing discussion demonstrates that a long-felt need continues to exist for improvements to angioplasty materials and/or methods, and/or for adjunct therapies, to reduce instances of restenosis.